Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, United States.
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, United States.
Am J Physiol Renal Physiol. 2023 Oct 1;325(4):F519-F526. doi: 10.1152/ajprenal.00105.2023. Epub 2023 Aug 17.
Endothelial cells play a key role in maintaining homeostasis and are deranged in many disease processes, including fibrotic conditions. Absence of the endothelial glucocorticoid receptor (GR) has been shown to accelerate diabetic kidney fibrosis in part through upregulation of Wnt signaling. The mouse model is a model of spontaneous type 2 diabetes that has been noted to develop fibrosis in multiple organs over time, including the kidneys. This study aimed to determine the effect of loss of endothelial GR on organ fibrosis in the model. mice lacking endothelial GR showed more severe fibrosis in multiple organs compared with endothelial GR-replete mice. Organ fibrosis could be substantially improved either through administration of a Wnt inhibitor or metformin. IL-6 is a key cytokine driving the fibrosis phenotype and is mechanistically linked to Wnt signaling. The model is an important tool to study the mechanisms of fibrosis and its phenotype in the absence of endothelial GR highlights the synergistic effects of Wnt signaling and inflammation in the pathogenesis or organ fibrosis. The major finding of this work is that endothelial glucocorticoid receptor-mediated upregulation of Wnt signaling and concurrent hyperinflammation work synergistically to exacerbate organ fibrosis in a genetic mouse model of diabetes. This study adds to our understanding of diabetic renal fibrosis and has important implications for the use of metformin in this condition.
内皮细胞在维持内环境稳定方面发挥着关键作用，在许多疾病过程中，包括纤维化疾病中，内皮细胞会发生紊乱。研究表明，缺乏内皮糖皮质激素受体 (GR) 会通过上调 Wnt 信号通路加速糖尿病肾病纤维化。该 小鼠模型是一种自发性 2 型糖尿病模型，随着时间的推移，其多个器官（包括肾脏）会逐渐发生纤维化。本研究旨在确定内皮 GR 缺失对 模型中器官纤维化的影响。与内皮 GR 丰富的 小鼠相比，缺乏内皮 GR 的 小鼠多个器官的纤维化更为严重。通过给予 Wnt 抑制剂或二甲双胍治疗，可显著改善器官纤维化。IL-6 是一种关键的细胞因子，可驱动纤维化表型，并且与 Wnt 信号通路在机制上相关。该 模型是研究纤维化及其在缺乏内皮 GR 时的表型的重要工具，这突出了 Wnt 信号和炎症在器官纤维化发病机制中的协同作用。这项工作的主要发现是，内皮糖皮质激素受体介导的 Wnt 信号上调和同时发生的过度炎症协同作用，可加剧糖尿病遗传小鼠模型中的器官纤维化。本研究增加了我们对糖尿病肾病纤维化的理解，并对二甲双胍在这种情况下的应用具有重要意义。
